Chronic Non-Healing Wounds: Clinically, wounds are categorized as acute or chronic based on the timeliness of healing. The normal response to tissue injury is a timely and orderly reparative process that results in sustained restoration of anatomic and functional integrity. In contrast, in chronic ulcers, the healing process is prolonged, incomplete, and proceeds in a disorganized manner resulting in poor anatomical and functional outcome. Most chronic ulcers are associated with a small number of well-defined clinical diseases particularly chronic venous hypertension, diabetes mellitus, and pressure ulcers. These conditions are responsible collectively for approximately 70% of all chronic ulcers. The incidence of chronic ulcers continues to increase because of such factors as increased longevity and the logarithmic increase in the incidence of Type II Diabetes throughout the world. In addition to these non-healing skin wounds, there are many other conditions characterized by excessive protease activity and disease chronicity, for example, oral inflammatory diseases such as gingivitis.
Pressure ulcers are an example of a chronic wound. They are characterized by deep tissue necrosis with loss of muscle and fat that is disproportionately greater than the loss of overlying skin. The incidence and prevalence of chronic pressure ulcers vary considerably but are especially high in spinal cord injury patients as well as the elderly and nursing home populations. Health care expenditures for treating pressure ulcers alone had been estimated to exceed $3 billion a year. Wound care is a significant part of the cost. Moreover, the incidence of pressure ulcers increases yearly worldwide because of increased longevity and trauma. There is similar data for diabetic wounds. The number of these wounds is increasing substantially because of an aging population, obesity and subsequent increased incidence of type II diabetes throughout the world.
Proteolytic Environment of Chronic Wounds: Normal healing involves a complex cascade of events involving interaction among many cell types, soluble factors and matrix components. Healing can be divided arbitrarily into overlapping temporal phases of coagulation, inflammation, fibroplasia, and finally remodeling. Cytokines (growth factors) are universally believed to be essential regulators for the repair process. Therefore, destruction of cytokines by proteases may retard healing. Normally, during the inflammatory phase, polymorphonuclear leukocytes (PMNs) are the first of the leukocytes to appear. They produce various proteases such as collagenase (MMP-8) and elastase, which help to remove damaged matrix and aid in healing. In both the acute and the chronic wounds, various cytokines are important in angiogenesis, contraction, collagen synthesis/degradation and subsequent wound closure. Under normal circumstances, closure of the open wound is aided further by epithelial (keratinocyte) cells which seal the wound for final closure. The healing of the chronic wounds is very different than normal healing. The same proteases which are part of the normal healing process become excessive because of the continued high levels of PMNs. These proteases then destroy matrix, growth factors and growth factor receptor sites. The pressure sore will be used for illustration of the chronic wound.
Neutrophils are the predominant infiltrating inflammatory cell type present in the acute inflammatory response. Neutrophils function primarily to destroy invading pathogens and to debride devitalized tissue at the site of injury. The normal adult produces approximately 1011 neutrophils per day. To function effectively in host defense, they must migrate to the site of inflammation and release selectively a large repertoire of proteolytic enzymes, antimicrobial peptides and potent oxidants from cytoplasmic granules. Under other conditions, the neutrophil has been implicated in causing disease by damaging normal host tissue. Such inflammatory tissue injury is important in the pathogenesis of a variety of clinical disorders including arthritis, ischemia-reperfusion tissue injury and systemic inflammatory response syndrome (SIRS) and the acute respiratory distress syndrome (ARDS). There is strong evidence that neutrophils also may have a significant role in the pathophysiology of chronic wounds.
Neutrophils are a prevalent cell type in pressure ulcers and other chronic wounds. In addition, there is direct evidence correlating neutrophil products with chronic pressure ulcers. Therefore, these observations have led to the hypothesis that neutrophil products are involved significantly in the pathogenesis of pressure sores and their subsequent failure to heal.
Neutrophils contain large amounts of elastase (1 pg/(cell). This serine protease is elevated significantly in fluid derived from pressure ulcers and other chronic wounds. The presence of high levels of active elastase within a wound site has important implications for ulcer pathogenesis and subsequent failure to heal. For example, elastase present in chronic wounds can degrade peptide growth factors such as PDGF and TGF-β. Moreover, cell surface receptors for peptide growth factors may themselves be functionally inactivated by the actions of elastase. Therefore, treatment of chronic wounds with growth factors is ineffective in the presence of high levels of elastase. Clinically, platelet derived growth factor (PDGF) fails to effectively promote healing of pressure sores because these wounds contain high levels of elastase (which destroys PDGF). In addition, elastase is known to proteolytically inactivate the specific inhibitor Tissue Inhibitor of Metalloproteinases (TIMP). Therefore, collagenase activity may actually become greater to further retard healing. In addition, elastase itself may participate in proteolytically activating collagenase and gelatinase zymogens.
Chronic wound treatments: Over the past two decades, many manufacturers have marketed “advanced wound care products” for the management of various chronic wounds. These include hydrocolloids, hydrogels and calcium alginates. However, there is little evidence that the rate of healing or cell biology of the wound has been altered by these products. In fact, in wet wounds, it is quite appropriate to use a dressing that is dry when placed in the wound.
There has been some activity in the patent literature thus far disclosing some approaches relating to wounds, as evidenced by the following.
U.S. Pat. No. 3,238,100 (issued Mar. 1, 1966) by Meyer et al., titled “Starch phosphate film composition and method of dressing wounds with same” discloses utility of a phosphorylated starch in wound healing. He reported that phosphorylated starches could be blended with regular starch, gelatin, pectin or carboxymethylcellulose to form strong transparent films. Apparently in the absence of phosphorylated starch, one cannot get clear strong films from starch and gelatin due to the lack of compatibility. Meyer described making a transparent film by dissolving a conventional phosphorylated starch in water with and without gelatin and casting 3-mil films. After sterilization, he compared healing performance of his clear film dressings against conventional gauze containing petroleum gel on burn wounds in dogs. Meyer described films prepared from the phosphorylated starches and their utility in wound healing. Meyer et al. also refer to the starch phosphate derivatives of U.S. Pat. Nos. 2,884,412; 2,884,413 and 2,993,041.
U.S. Pat. No. 4,225,580 (issued Sep. 30, 1980) and U.S. Pat. No. 4,537,767 (issued Aug. 27, 1985) both by Rothman et al., titled “Method for cleansing fluid discharging skin surfaces, wounds and mucous membranes and means for carrying out the method.”
U.S. Pat. No. 6,156,334 (issued Dec. 5, 2000) by Meyer-Ingold et al., titled “Wound coverings for removal of interfering factors from wound fluid.”
U.S. Pat. No. 6,306,419 (issued Oct. 23, 2001) by Vachon et al. (Aegis Biosciences, LLC), titled “Medical uses of styrene sulfonate polymers” discloses use of silver as a therapeutic agent for wound dressings. They teach use of silver to impart antimicrobial activity to coated fabrics. They describe that when a fabric is coated with a styrene sulfonate polymer and then equilibrated with soluble silver solution until silver is partially reduced to metallic silver, the fabric becomes antimicrobial.
U.S. Pat. No. 6,599,523 (issued Jul. 29, 2003) by Cohen et al., titled “Preparation of peroxide-oxidized, sulfonated, and phosphorylated cotton.”
U.S. Pat. No. 6,627,785 (issued Sep. 30, 2003) by Edwards et al., titled “Wound dressings with protease-lowering activity.”
U.S. Pat. No. 6,911,437 (issued Jun. 28, 2005) by Edwards et al., titled “Saccharide derivatives especially useful in wound dressings.”
However, the present inventors have considered the state of the art and find that there still remain needs for better materials to promote wound healing for various kinds of wounds. For example, conventional wound dressings generally suffer from one or more of the problems of not swelling much to absorb fluid, little or no elastase and collagenese sequestering and/or loss of silver content (if any) upon a first washing.